The present invention relates to a process of producing an anti-thrombogenic material. More particuarly, the present invention relates to a process for producing a medical material having high anti-thrombogenicity by grafting a hydrophilic monomer onto a high-molecular weight substrate.
A variety of high-molecular weight materials have been used as medical materials. However, these material are foreign to living organisms and if they are used in direct contact with blood, they induce blood coagulation and cause occlusion or deposition of blood clot. These are highly undesirable phenomena that impair the capabilities of these high-molecular weight materials when used in medical devices. Therefore, a strong need exists to develop anti-thrombogenic materials that will not induce blood coagulation.
Various approaches have been taken in the efforts toward developing anti-thrombogenic medical materials. One of the methods under review is to support anticoagulants on high-molecular weight materials. However, the amount of anticoagulants that can be supported by this method is limited and, in addition, the short life of available anticoagulants makes it unrealistic to anticipate prolonged anti-thrombogenic effects. In an attempt at imparting anti-thrombogenicity to high-molecular weight materials per se, the idea of introducing a macro-domain dispersive structure has been investigated. This method is effective in preventing the activation of deposited platelets and coagulation factors but is not equally effective against already activated blood; in other words, the efficacy of this method is not consistent.
In order to prevent blood coagulation, it is most effective to prevent the occurrence of physiochemical interactions between coagulation factors in the blood and high-molecular weight substrates. The walls of blood vessels in living organisms have carbohydrate chains on the surfaces of their cell membrances that exhibit similar effects in preventing interactions with blood. Methods based on this idea have been proposed by Hoffman et al. (Trans. Amer. Soc. Artif. Int. Organs, 1972, Vol. XVIII, pp 10-17) and Ikada et al. (Jinko Zoki, 15, 1, pp 12-15, 1986) and consist of forming highly hydrophilic and mobile polymer chains on the surface of a high-molecular weight substrate, thereby constructing a diffuse surface that prevents interactions between living tissues and the substrate. The efforts directed to those methods center on techniques that employ graft polymerization and many monomers including 2-hydroxyethyl methacrylate (HEMA) and acrylamide (AAm) have been reviewed as candidate grafts. The results of such reviews are described in prior patents such as Japanese Patent Publication Nos. 32554/1975, 15556/1978 and 43563/1982, and Unexamined Published Japanese Patent Application Nos. 72294/1979, 5320/1983 and 45328/1984.
However, the methods disclosed in these patents are all directed to the formation of a hydrogel layer. Hydrogels have a large amount of water confined in crosslinked polymer chains and their mechanical strength is comparatively low. Furthermore, the mobility of the polymer chains is not necessarily high and their interactions with blood components are not completely eliminated [see B. D. Ratnar et al., J. Polym. Sci.: Polym. Symp., 66, 363-375 (1979) and A. Nakao et al., Jinko Zoki, 13, 3, pp 1151-1154 (1984)]. Therefore, in order to construct an effective diffuse surface having high anti-thrombogenicity, efficient formation of a long chain of polymers in a highly hydrated state is desired and it is necessary to avoid undue deterioration of physical strength. Preclinical studies have been conducted with a view to constructing anti-thrombogenic surfaces by graft polymerization and improved anti-thrombogenicity data from animal experiments have been reported (K. Hayashi et al., Kobunshi Ronbunshu, vol. 39, pp 179-182, 1982, and vol. 42, pp 77-83, 1985). Therefore, graft polymerization holds most promise as a technique for constructing anti-thrombogenic surfaces.